1-Tertiary-alkyl-3-(substituted thienyl)ureas and 1-tertiary-alkyl-3-(substituted thietyl)ureas as antihypertensive agents

ABSTRACT

This invention relates to a class of 1-tertiary-alkyl-3-(substituted thienyl)ureas and 1-tertiary-alkyl-3-(substituted thietyl)ureas that exhibit antihypertensive activity in warm-blooded animals. Representative compounds are 1-tert-butyl-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide and 1-tert-butyl-3-(3-thiethyl)urea S,S-dioxide.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of my copending applicationSer. No. 461,699, filed Apr. 17, 1974 now abandoned.

BACKGROUND OF THE INVENTION

It is well known that certain guanidine derivatives of tert-carbinaminespossess antihypertensive (hypotensive) activity. Specific examples aretert-alkyl cyanoguanidines such as 1-tert-amyl-3-cyanoguanidine asdescribed in S. M. Gadekar, S. Nibi, and E. Cohen, J. Med. Chem., 11,811 (1968); and various derivatives of tert-alkyl guanidines such astert-butyl guanidine, as described in J. H. Short, C. W. Ours, W. J.Ranus, Jr., J. Med. Chem., 11 1129 (1968).

However, urea derivatives are not represented in comprehensivediscussions of antihypertensive agents. Such comprehensive discussionsinclude W. T. Comer and A. W. Gomoll, Medicinal Chemistry, ThirdEdition, A. Burger, Wiley-Interscience, New York, 1970, pp. 1019-1064;and Medicinal Chemistry, Volume 7, "Antihypertensive Agents", E.Schlittler, Academic Press, New York, 1967. The urea-derivativecompounds of this invention provide effective treatment of hypertension,yet differ structurally and chemically over antihypertensive agentscurrently known.

SUMMARY OF THE INVENTION

This invention relates to (a) compounds represented by the formula##STR1## where

R₁, R₂ and R₃ are C₁ -C₃ alkyl or C₂ -C₃ alkenyl, with the provisos thatthe total number of carbon atoms of R₁ plus R₂ plus R₃ does not exceed5, and that two of R₁, R₂, and R₃ may be joined to form a cycloalkyl orcycloalkenyl group; ##STR2##

R₄ is H or CH₃ with the proviso that when R₄ is CH₃, X is -CH₂ - or -CH₂CH₂ -; and

(B) SODIUM, POTASSIUM OR CALCIUM SALTS OF COMPOUNDS OF (A),

Preferred compounds within the scope of the above definition includethose wherein R₁, R₂, and R₃ are C₁ -C₃ alkyl.

Another embodiment of the invention relates to a method for treatinghypertension in warm-blooded animals which comprises administering tosaid animal an antihypertensive amount of a compound of the invention.

Still another embodiment of the invention relates to pharmaceuticalcompositions which contain a compound of the invention in combinationwith suitable pharmaceutical adjuvants and modifiers.

DETAILED DESCRIPTION OF THE INVENTION

As indicated above, compounds of the invention include those of theformula ##STR3## wherein

R₁, R₂, R₃, R₄ and X are as previously defined. It is also to beunderstood that metal salts of the above-defined compounds are includedwithin the scope of this invention. Illustrative of such metals aresodium, potassium and calcium. These salts are readily hydrolyzed toyield the respective free compounds.

The compounds of this invention are readily prepared as represented bythe following equation: ##STR4##

The compounds are prepared by heating equimolar amounts of the reactantsin benzene with provision for water removal as, for example, aDean-Stark water separator. In many cases water removal is notnecessary. A catalytic amount of a strong acid (e.g., p-toluenesulfonicacid) is usually added to hasten the reaction. Although benzene is thepreferred solvent, other solvents can be employed as, for example,toluene. Refluxing is continued until no more water is condensed in theDean-Stark trap. Often the product precipitates during the course of thereaction and can subsequently be removed by filtration. Otherwise, it isisolated by chromatography and/or crystallization.

The salts of the compounds of this invention can be prepared by treatingthe compound with an alcoholic or aqueous solution of an equimolaramount of the respective alkali hydroxide and evaporating to dryness. Ingeneral, because the salts of these compounds hydrolyze readily, suchsalts are less desirable for use in formulating pharmaceuticalcompositions of the invention than the compounds per se.

The preparation of the compounds of this invention is illustrated butnot limited by the following examples.

EXAMPLE 1 1-tert-butyl-3-(4,5-dihydro-3-thienyl)urea S,S-Dioxide

To a solution of 6.7 g 3-oxo-tetrahydrothiophene S,S-dioxide [(J. Chem.Soc. (C), 2171 (1967)] in 100 ml of benzene is added 5.6 g of tert-butylurea and 100 mg p-toluene acid. The solution is heated at reflux undernitrogen with water removal for three hours. At the end of this periodthe solution is cooled and concentrated. The residual material isrecrystallized from acetonitrile to give 6.8 g of1-tert-butyl-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide, m.p. 195°-197°C.

The infrared and n.m.r. spectra are consistent with the assignedstructure.

EXAMPLES 2-12

Using the procedure described in Example 1, the reactants shown incolumn 1 produce the respective products of this invention as shown incolumn 2. In some cases it is preferable to purify the product usingchromatography.

    __________________________________________________________________________    Example  Reactants                  Products                                  __________________________________________________________________________              ##STR5##                                                                                                m.p. 184- 186° C.                  3                                                                                       ##STR7##                                                                     m.p. 210° C (dec)                                             4                                                                                       ##STR9##                                                                     m.p. 172-174° C                                               5                                                                                       ##STR11##                                                           6         ##STR12##                                                                     ##STR13##                                                           7         ##STR14##                                                                     ##STR15##                                                           8         ##STR16##                                                                     ##STR17##                                                           9         ##STR18##                                                                     ##STR19##                                                           10        ##STR20##                                                                     ##STR21##                                                                    m.p. 197° C (dec.)                                            11                                                                                      ##STR23##                                                           12        ##STR24##                                                                     ##STR25##                                                                     ##STR26##                                                           __________________________________________________________________________

EXAMPLE 13 1-tert-butyl-3-(4-methyl-4,5-dihydro-3-thienyl)ureaS,S-dioxide

To a solution of 6.4 g of 4-methyl-3-oxo-tetrahydrothiophene S,S-dioxide(E. Eigenberger, J. Prakt, Chem. 127, 307 (1930) in 100 ml benzene isadded 6.0 g of tert-butyl urea and 100 mg p-toluenesulfonic acid. Thesolution is heated at reflux under nitrogen with water removal using aDean-Stark trap for 18 hours. At the end of this period the solution iscooled and concentrated. The residual material is chromatographed on 400g of silicic acid using benzeneethyl acetate-methanol (6:3:1). Thecrystalline product obtained after chromatography is recrystallized fromacetonitrile to give 4.5 g of1-tert-butyl-3-(4-methyl-4,5-dihydro-3-thienyl)urea S,S-dioxide, m.p.195° C dec. The structure is confirmed by infrared and n.m.r. spectraand elemental analysis.

EXAMPLES 14-17

Using the procedure described in Example 13, the reactants shown incolumn 1 produce the respective products of this invention as shown incolumn 2.

    __________________________________________________________________________    Example                                                                            Reactants              Products                                          __________________________________________________________________________    14                                                                                  ##STR27##                                                                    m.p. 178° C. (dec.)                                               15                                                                                  ##STR29##                                                                    m.p. 174-176° C                                                   16                                                                                  ##STR31##                                                                    m.p. 122-124° C                                                   17                                                                                  ##STR33##                                                                    m.p. 167-169° C (dec.)                                            __________________________________________________________________________

EXAMPLE 18 1-tert amyl-3-(2-methyl-4,5-dihydro-3-thienyl)ureaS,S-dioxide

This compound is prepared in three steps as follows:

1. To a solution of 18 g 3-oxo-tetrahydrothiopene S,S-dioxide in 150 mlbenzene is added 15 g of pyrrolidine and 100 mg p-toluenesulfonic acid.The solution is heated at reflux under nitrogen with water removal forfour hours. The solution is cooled and the gummy precipitate is filteredand recrystallized from acetonitrile to give 15 g of3-pyrrolidino-4,5-dihydro-3-thiene S,S-dioxide, m.p. 148°-150°(decomp.). The structure is confirmed by infrared n.m.r. spectra andelemental analysis.

2. To a solution of 12 g of 3-pyrrolidine-4,5-dihydro-3-thieneS,S-dioxide in 50 ml dioxane is added 20 ml of methyl iodide. Thesolution is heated at reflux under nitrogen with stirring for 20 hours.At one end of this period 25 ml of water and 3 ml of acetic acid areadded and one solution is heated at reflux for six hours. At the end ofthis period, the solution is cooled and concentrated. The residualmaterial is extracted with three 150 ml portions of boiling benzene. Thebenzene solution is concentrated and one residual material ischromatographed on 100 g of silicic acid. Elution with a solution ofethyl acetate, toluene, hexane (6:3:1) gives a crystalline material.This material is recrystallized from ethanol to give2-methyl-3-oxotetrahydrothiophene S,S-dioxide, m.p. 83°-85° C. Thestructure is confirmed by infrared and n.m.r. spectra and elementalanalysis.

3. Replacing 4-methyl-3-oxo-tetrahydrothiophene S,S-dioxide in Example13 by 2-methyl-3-oxo-tetrahydrothiophene S,S-dioxide gives 1-tertamyl-3-(2-methyl-4,5-dihydro-3-thienyl)urea S,S-dioxide, m.p. 160°- 162°C. The structure is confirmed by infrared and n.m.r. spectra anelemental analysis.

EXAMPLE 19 1-tert amyl-3-(5-methyl-4,5-dihydro-3-thienyl)ureaS,S-dioxide

5-Methyl-3-oxo-tetrahydrothiophene S,S-dioxide, one of the startingmaterials for synthesis of 1-tertamyl-3-(5-methyl-4,5-dihydro-3-thienyl)urea S,S-dioxide, is prepared asfollows: ##STR35##

The procedure of Example 13 is used except that4-methyl-3-oxo-tetrahydrothiophene S,S-dioxide is replaced with5-methyl-3-oxo-tetrahydrothiophene S,S-dioxide to give1-tert-amyl-3-(5-methyl-4,5-dihydro-3-thienyl)urea S,S,-dioxide.

EXAMPLES 20-28

Using the procedure described in Example 13, the reactants shown incolumn 1 produce the respective products of this invention as shown incolumn 2. The 3-thietanone S,S-dioxide starting material is prepared asdescribed by Truce and Campbell, J. Am. Chem. Soc. 88, 3599 (1966).

    __________________________________________________________________________    Example                                                                            Reactants              Products                                          __________________________________________________________________________    20                                                                                  ##STR36##                                                                    m.p. 180-181° C                                                                               (dec.)                                            21                                                                                  ##STR38##                                                                    m.p. 180° C (dec.)                                                22                                                                                  ##STR40##                                                               23    ##STR41##                                                                     ##STR42##                                                               24    ##STR43##                                                                     ##STR44##                                                               25    ##STR45##                                                                     ##STR46##                                                                    m.p. 182° C (dec.)                                                26                                                                                  ##STR48##                                                                    27#STR49##                                                                                            ##STR50##                                        28                           ##STR51##                                              ##STR52##                                                                     ##STR53##                                                               __________________________________________________________________________

EXAMPLES 29-33

Using the procedure described in Example 13, the reactants shown incolumn I produce the respective products of this invention as shown incolumn II. The 2-methyl-3-thietanone S,S-dioxide starting material isprepared as described by M. H. Rosen, Tet. Letters 8, 647-650 (1969).

    __________________________________________________________________________           I                      II                                              Examples                                                                           Reactants               Product                                          __________________________________________________________________________    29                                                                                  ##STR54##                                                               30    ##STR55##                                                                     ##STR56##                                                                    dimorphic: m.p. 120-122°                                                                       and m.p. 140-141° C                       31                                                                                  ##STR58##                                                                    m.p. 153-154° C                                                   32                                                                                  ##STR60##                                                               33    ##STR61##                                                                     ##STR62##                                                                     ##STR63##                                                               __________________________________________________________________________

The compounds of this invention can be administered in the treatment ofhypertension according to the invention by any means that effectscontact of the active ingredient compound with the site of action in thebody of a warm-blooded animal. For example, administration can beparenteral, i.e., subcutaneous, intravenous, intramuscular, orintraperitoneal. Alternatively or concurrently, administration can be bythe oral route.

For the purpose of this disclosure, a warm-blooded animal is a member ofthe animal kingdom possessed of a homostatic mechanism and includesmammals and birds.

The dosage administered will be dependent on the age, health, and weightof the receipient, the extent of disease, kind of concurrent treatment,if any, frequency of treatment, and the nature of the effect desired.Usually, a daily dosage of active ingredient compound will be from about0.1 to 50 milligrams per kilogram of body weight. Ordinarily, from 0.5to 40, and preferably, 1.0 to 20, milligrams per kilogram per day in oneor more applications per day is effective to obtain desired results. Forthe more potent compounds of the invention, e.g.,1-tert-amyl-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide, the daily dosageranges are from about 0.1 to 20 mg/kg, preferably 0.5 to 15 mk/kg, andmore preferably 1.0 to 10 mg/kg.

The antihypertensive activity of the compounds of this invention isevidenced by tests conducted in hypertensive rats and by further testswhich show a blood pressure lowering effect in normotensive dogs.

In these tests rats are made hypertensive by repeated injections ofdesoxycorticosterone acetate (DOCA) and by giving the rats salinesolution to drink essentially according to the method described byStanton and White [Arch. Intern. Pharmacodyn., 154, 351 (1965)]. Gradeddose levels of each compound are administered orally to groups of eighthypertensive rats. The compound is prepared in a aqueous polyvinylalcohol/acacia vehicle and administered at a volume to body weight ratioof 5.0 ml/kg. Sixteen hypertensive rats receiving the aqueous vehicle bythe same route serve as controls for each test. At various intervals oftime after treatment, usually 90 minutes, the systolic arterial bloodpressure of each rat is determined by a modification of themicrophone-manometer technique [Friedman, M. and Freed, S. C., Proc.Soc. Exp. Biol. and Med., 70, 670 (1969)]. That dose of compound whichproduces a 30 mm mercury (mm Hg) reduction in blood pressure whencompared to the mean systolic arterial blood pressure of the controlanimals is then determined (Effective Dose 30). For example, an ED30 of6.0 mg/kg orally was obtained with1-tert-amyl-3-(4,5-dihydro-3-thienyl)urea, S,S-dioxide. An ED₃₀ of 12.0was obtained with 1-tert-butyl-3-(4,5-dihydro-3-thienyl)ureaS,S-dioxide. An ED₃₀ of 1.7 was obtained with 1-tert-amyl(4-methyl-4,5-dihydro-3-thienyl) urea S,S-dioxide.

In a test involving dogs, these compounds are administered intravenously(i.v.) to eight anesthetized normotensive dogs according to a cumulativedose schedule. Arterial blood pressure is recorded directly through anarterial cannula and a polygraph by which it is determined that thecompound shows statistically significant blood pressure lowering incomparison to the predosing control value and to the effect of vehicleon control animals.

The compounds of this invention can be employed in useful pharmaceuticalcompositions according to the present invention in such dosage forms astablets, capsules, powder packets, or liquid solutions, suspensions orelixirs for oral administration or liquid for parenteral use, and incertain cases, suspensions for parenteral use (except intravenousinjections). In such compositions, the active ingredient will ordinarilyalways be present in an amount of at least 0.5% by weight based on thetotal weight of the composition and not more than 95% by weight.

Besides the active ingredient compounds of this invention, theantihypertensive composition will contain a solid or liquid non-toxicpharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, thesolid carrier is a capsule which can be of the ordinary gelatin type. Inthe capsules will be from about 5 to 90% by weight of a compound of theinvention and 95 to 10% of a carrier. In another embodiment, the activeingredient is tableted with or without adjuvants. In yet anotherembodiment, the active ingredient is put into powder packets andemployed. These capsules, tablets, and powders will generally constitutefrom about 1% to about 95% and preferably from 5% to 90% by weight ofactive ingredient. These dosage forms preferably contain from about 5 to500 milligrams of active ingredient, with about 7 to about 250 mostpreferred.

The pharmaceutical carrier can, as previously indicated, be a sterileliquid such as water and oil, including those of petroleum, animal,vegetable oils of synthetic origin, for example peanut oil, soybean oil,mineral oil, sesame oil, and the like. In general, water saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are preferred liquid carriers,particularly for injectible solutions. Sterile injectible solutions,such as saline, will ordinarily contain from about 0.5% to 25% andpreferably about 1 to 10% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspensionor syrup, in which the active ingredient ordinarily will constitute fromabout 0.7 to 10% and preferably about 1 to 5%, by weight. Thepharmaceutical carrier in such composition can be a watery vehicle suchas an aromatic water, a syrup, or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in "Remington'sPharmaceutical Sciences" by E. W. Martin, a well-known reference text inthis field.

The following examples will further illustrate the preparation ofpharmaceutical compositions of the invention.

EXAMPLE A

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 250 milligrams of powdered1-tert-butyl-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide, 110 milligramsof lactose, 32 milligrams of talc, and 8 milligrams of magnesiumstearate.

EXAMPLE B

A mixture of 1-tert-amyl-3-(4,5-dihydro-3-thienyl) urea S,S-dioxide insoybean oil is prepared and injected by means of a positive displacementpump into gelatin to form soft gelating capsules containing 35milligrams of the active ingredient. The capsules are washed inpetroleum ether and dried.

EXAMPLE C

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 milligrams of active ingredient, 7milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicondioxide, 7 milligrams of magnesium stearate, 11 milligrams ofmicrocrystalline cellulose, 11 milligrams of cornstarch, and 98.8milligrams of lactose. Appropriate coatings may be applied to increasepalatability or delay absorption.

EXAMPLE D

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of1(1-methylcyclopentyl)-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide in 10%by volume propylene glycol and water. The solution is sterilized byfiltration.

EXAMPLE E

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 50 milligrams of finely divided1-tert-butyl-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide, 500 milligramsof acacia, 5 milligrams of sodium benzoate, 1.0 grams of sorbitolsolution, U.S.P., 5 milligrams of sodium saccharin, and 0.025milliliters of vanilla tincture.

EXAMPLE F

A parenteral composition suitable for administration by injection isprepared by dissolving 1% by weight of1-tert-amyl-3-(4,5-dihydro-3-thienyl)urea. S,S-dioxide in sodiumchloride injection U.S.P. XV and adjusting the pH of the solution tobetween 6 and 7. The solution is sterilized by filtration.

A wide variety of compositions coming within this invention can beprepared by substituting other compounds of this invention, includingspecifically but not limited to those compounds named hereinbefore, forthe compounds named in Examples A-F above and substituting othersuitable pharmaceutical carriers well known and described in the Martintext mentioned above.

What is claimed is:
 1. A compound of the formula: ##STR64##where R₁, R₂and R₃ are C₁ -C₃ alkyl, or C₂ -C₃ alkenyl, with the provisos that thetotal number of carbon atoms of R₁ plus R₂ plus R₃ does not exceed 5##STR65##R₄ is H or CH₃ with the proviso that when R₄ is CH₃, X is -CH₂CH₂ -; and its sodium, potassium, or calcium salts.
 2. The compound ofclaim 1 wherein R₁, R₂, and R₃ are C₁ -C₃ alkyl.
 3. The compound ofclaim 2 which is 1-tert-butyl-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide.4. The compound of claim 2 which is1-tert-amyl-3-(4,5-dihydro-3-thienyl)urea S,S-dioxide.
 5. The compoundof claim 2 which is 1-tert-amyl-3-(4-methyl-4,5-dihydro-3-thienyl)ureaS,S-dioxide.
 6. A method of treating hypertension in a warm-bloodedanimal comprising administering to the warm-blooded animal an effectiveantihypertensive amount of a compound of claim
 1. 7. A method oftreating hypertension in a warm-blooded animal comprising administeringto the warm-blooded animal an effective antihypertensive amount of acompound of claim
 2. 8. A method of treating the hypertension in awarm-blooded animal comprising administering to the warm-blooded animalan effective antihypertensive amount of a compound of claim
 3. 9. Amethod of treating hypertension in a warm-blooded animal comprisingadministering to the warm-blooded animal an effective antihypertensiveamount of a compound of claim
 4. 10. A method of treating hypertensionin a warm-blooded animal comprising administering to the warm-bloodedanimal an effective antihypertensive amount of a compound of claim 5.11. A pharmaceutical composition comprising a suitable pharmaceuticalcarrier and an effective antihypertensive amount of a compound ofclaim
 1. 12. A pharmaceutical composition comprising a suitablepharmaceutical carrier and an effective antihypertensive amount of acompound of claim
 2. 13. A pharmaceutical composition comprising asuitable pharmaceutical carrier and an effective antihypertensive amountof a compound of claim
 3. 14. A pharmaceutical composition comprising asuitable pharmaceutical carrier and an effective antihypertensive amountof a compound of claim
 4. 15. A pharmaceutical composition comprising asuitable pharmaceutical carrier and an effective antihypertensive amountof a compound of claim 5.